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A M Walker

Publications and source records attributed to A M Walker.

At least 19 recordsLinked to original sources
PubMed2006

Multilevel modelling of the incidence of visceral leishmaniasis in Teresina, Brazil.

Epidemics of visceral leishmaniasis (VL) in major Brazilian cities are new phenomena since 1980. As determinants of transmission in urban settings probably operate at different geographic scales, and information is not available for each scale, a multilevel approach was used to examine the effect of canine infection and environmental and socio-economic factors on the spatial variability of incidence rates of VL in the city of Teresina. Details on an outbreak of greater than 1200 cases of VL in Teresina during 1993-1996 were available at two hierarchical levels: census tracts (socio-economic characteristics, incidence rates of human VL) and districts, which encompass census tracts (prevalence of canine infection). Remotely sensed data obtained by satellite generated environmental information at both levels. Data from census tracts and districts were analysed simultaneously by multilevel modelling. Poor socio-economic conditions and increased vegetation were associated with a high incidence of human VL. Increasing prevalence of canine infection also predicted a high incidence of human VL, as did high prevalence of canine infection before and during the epidemic. Poor socio-economic conditions had an amplifying effect on the association between canine infection and the incidence of human VL. Focusing interventions on areas with characteristics identified by multilevel analysis could be a cost-effective strategy for controlling VL. Because risk factors for infectious diseases operate simultaneously at several levels and ecological data usually are available at different geographical scales, multilevel modelling is a valuable tool for epidemiological investigation of disease transmission.

Animals↗
PubMed2006

Physico-chemical and biological characterizations of two human prolactin analogs exhibiting controversial bioactivity, synthesized in Chinese hamster ovary (CHO) cells.

The synthesis, purification and characterization of G129R-hPRL and S179D-hPRL, the two better-studied antagonists of human prolactin (hPRL), is described. Both of these have been expressed for the first time, in their authentic form, by a stable CHO cell line, at secretion levels of 7.7 and 4.3 microg/10(6) cells/day, respectively. Previous studies had shown that these hPRL analogs, when produced in bacterial cytoplasm, consistently contained misfolded forms and multimers according to the specific denaturation, refolding and purification conditions. These versions also have an N-terminal extra methionine. An extensive physico-chemical characterization was carried out after a practical two-step purification process and included SDS-PAGE and Western blotting analysis, matrix-assisted laser-desorption ionization time-of-flight mass spectral (MALDI-TOF-MS) analysis, high-performance size-exclusion chromatography (HPSEC) and reversed-phase high-performance liquid chromatography (RP-HPLC). This last technique revealed a considerable difference in hydrophobicity due to a single amino acid substitution, with S179D-hPRL less (t(RR) = 0.85 +/- 0.010) and G129R-hPRL more (t(RR) = 1.10 +/- 0.013) hydrophobic than hPRL, where t(RR) is the relative retention time. The biological characterization was based on further refinement of a sensitive proliferation assay using the pro-B murine cell line (Ba/F3) transfected with the long form hPRL receptor cDNA such that the minimal detectable dose was 0.04 ng of hPRL/mL, the Ba/F3-LLP assay. On the basis of this assay, the relative residual agonistic activity of these two products, determined against a hPRL international standard in four independent assays, was 53 x 10(-3) for S179D-hPRL and 70 x 10(-5) for G129R-hPRL. We believe that the present synthesis and characterization could be extremely helpful for studies of these two proteins, which have been reported to antagonize tumor growth-promoting effects of hPRL in vivo in animal models of breast and prostate cancer.

Animals↗
PubMed2006

Risk factors for hospital-acquired methicillin-resistant Staphylococcus aureus bacteraemia: a case-control study.

A case-control study was undertaken in an acute district general hospital to identify risk factors for hospital-acquired bacteraemia caused by methicillin-resistant Staphylococcus aureus (MRSA). Cases of hospital-acquired MRSA bacteraemia were defined as consecutive patients from whom MRSA was isolated from a blood sample taken on the third or subsequent day after admission. Controls were randomly selected from patients admitted to the hospital over the same time period with a length of stay of more than 2 days who did not have bacteraemia. Data on 42 of the 46 cases of hospital-acquired bacteraemia and 90 of the 92 controls were available for analysis. There were no significant differences in the age or sex of cases and controls. After adjusting for confounding factors, insertion of a central line [adjusted odds ratio (aOR) 35.3, 95% confidence interval (CI) 3.8-325.5] or urinary catheter (aOR 37.1, 95% CI 7.1-193.2) during the admission, and surgical site infection (aOR 4.3, 95% CI 1.2-14.6) all remained independent risk factors for MRSA bacteraemia. The adjusted population attributable fraction, showed that 51% of hospital-acquired MRSA bacteraemia cases were attributable to a urinary catheter, 39% to a central line, and 16% to a surgical site infection. In the United Kingdom, measures to reduce the incidence of hospital-acquired MRSA bacteraemia in acute general hospitals should focus on improving infection control procedures for the insertion and, most importantly, care of central lines and urinary catheters.

Bacteremia↗
PubMed2005

Abrogation of delayed type hypersensitivity response to Candida albicans produced by a molecular mimic of phosphorylated prolactin.

The effects of two major forms of prolactin (PRL) were examined on delayed type hypersensitivity (DTH) responses to Candida albicans. Unmodified PRL (U-PRL) had no effect on the DTH response, whereas a molecular mimic of phosphorylated PRL (S179D PRL) significantly inhibited immune responses to this robust antigen. This effect of S179D PRL was not accompanied by gross alterations in splenic T cell numbers, CD4/CD8 ratios, or T and B cell activation markers, but did produce a decrease in splenocyte apoptosis. Using gld animals, Fas ligand (FasL) was implicated in the suppressive effects of S179D PRL. Circulating IgG1 and IgG2 antibody levels were increased in response to treatment with both forms of PRL, but the effects of S179D PRL were most pronounced. Cytokine changes in the popliteal lymph nodes specific to S179D PRL treatment showed an inhibition of pro-inflammatory cytokines. In conclusion, mice treated with a molecular mimic of phosphorylated prolactin showed a profound inhibition of DTH responses to Candida correlating with an absence of GM-CSF, IL-4, and IL-13 production and a marked reduction in IL-12p70 synthesis.

Animals↗
PubMed2005

Ganciclovir and acyclovir reduce the risk of post-transplant lymphoproliferative disorder in renal transplant recipients.

Given its association with Epstein-Barr virus (EBV), there is considerable interest in assessing the impact of prophylactic anti-viral therapy on post-transplant lymphoproliferative disorder (PTLD). A recently completed multi center case-control study assessed the impact of immunosuppressive therapy on PTLD risk among renal transplant patients and collected information on the use of anti-viral therapy. Biopsy-confirmed PTLD cases (n = 100) were matched to 375 controls by center, date of transplant, and age. Data were collected on immunosuppression and rejection therapies, demographics, pre-transplant viral status, number of rejections, and anti-viral use. With adjustment for known risk factors, prophylactic anti-viral use was associated with up to 83% reduction in the risk of PTLD, depending on the anti-viral agent. These results were stronger for the first year post-transplant. For every 30 days of ganciclovir treatment, risk of PTLD during the first year was lower by 38% (Odds Ratio [OR]= 0.62; 95% confidence interval [CI]= 0.38-1.0); acyclovir effects were less striking (OR = 0.83; 95% CI = 0.59-1.16). Anti-viral therapy appears to play a role in reducing the risk of PTLD in renal transplant patients. Ganciclovir may be more potent than acyclovir.

Acyclovir↗
PubMed2005

Treating pedal shortening in a dog by metatarsal distraction osteogenesis.

A five-month-old, male German shepherd dog was presented with a left hindlimb deformity. Wearing a cast for a prolonged period to treat left metatarsal fractures at eight weeks of age had resulted in physeal closure of the calcaneus, metatarsals and phalanges. Hyperextension of the phalanges and ulceration of the plantar skin proximal to the main tarsal pad were seen. The left foot was 40 mm shorter than the right. At seven months of age, a modified circular external skeletal fixator (CESF) was used to perform distraction osteogenesis of the metatarsal bones for 28 days. The CESF apparatus was removed after eight weeks when there was radiographic consolidation of regenerate bone. At follow-up evaluations four and 12 months after surgery, the phalangeal hyperextension and plantar skin ulceration had resolved. No lameness was detected.

Animals↗
PubMed2005

Prolactin, the prolactin receptor and uncoupling protein abundance and function in adipose tissue during development in young sheep.

A primary role of the prolactin receptor (PRLR) during fetal and postnatal development has been suggested to be the regulation of uncoupling protein (UCP) expression. We, therefore, determined whether: (1) the rate of loss of UCP1 from brown adipose tissue after birth was paralleled by the disappearance of PRLR; and (2) administration of either pituitary extract prolactin (PRL) containing a mixture of posttranslationally modified forms or its pseudophosphorylated form (S179D PRL) improved thermoregulation and UCP1 function over the first week of neonatal life. PRLR abundance was greatest in adipose tissue 6 h after birth before declining up to 30 days of age, a trend mirrored by first a gain and then a loss of UCP1. In contrast, in the liver--which does not possess UCPs--a postnatal decline in PRLR was not observed. Administration of PRL resulted in an acute increase in colonic temperature in conjunction with increased plasma concentrations of non-esterified fatty acids and, as a result, the normal postnatal decline in body temperature was delayed. S179D PRL at lower concentrations resulted in a transient rise in colonic temperature at both 2 and 6 days of age. In conclusion, we have demonstrated a close relationship between the ontogeny of UCP1 and the PRLR. Exogenous PRL administration elicits a thermogenic effect suggesting an important role for the PRLR in regulating UCP1 function.

Adipose Tissue↗
PubMed2004

Successful treatment of a pancreatic pseudocyst by omentalisation in a dog.

CASE HISTORY: A 3-year-old male Labrador retriever was presented with a history of dietary indiscretion followed by vomiting and abdominal pain. CLINICAL FINDINGS AND TREATMENT: Abdominal ultrasonography revealed the presence of a fluid-filled cystic structure in the region of the pancreas. Flocculent, dark fluid was drained from the cystic structure during exploratory celiotomy prior to resection of the lateral cystic wall. Omentum was sutured into the cystic cavity to provide drainage and enhance immune response. A jejunostomy feeding tube was placed. Post-surgical care consisted of antibiotic therapy. The dog was clinically normal at 1 and 7 months post-operatively and the pancreas appeared normal on final ultrasonographic examination. CLINICAL RELEVANCE: This case describes the use of omentum to provide physiological drainage of a pancreatic pseudocyst. This surgical technique may help clinicians manage patients with this condition in the future.

Journal Article↗
PubMed2004

Hepatitis B and hepatitis C seroprevalence and risk behaviour among community-recruited drug injectors in North West Wales.

We estimated the prevalence of markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and injecting risk behaviour, among community-recruited injecting drug users (IDUs) in North West Wales in 2001 and 2002. Sample collection was undertaken by trained current and former IDUs. Oral fluid samples (n = 153) were tested as part of the Unlinked Anonymous Prevalence Monitoring Programme ongoing survey of IDUs. Approximately 12% of the sample reported that they were currently in a drug treatment programme. Of the 153 samples screened 27% (95% CI 20%-34%, 41/153) were anti-HBc positive, and 23% (95% CI 16%-30%, 35/153) were anti-HCV positive. Sixteen per cent (95% CI 10%-22%, 25/ 153) of the samples were positive for both anti-HBc and anti-HCV. Of the subjects 15% (95% CI 9%-20%) knew they had been vaccinated against hepatitis B. Direct sharing of needles and syringes in the 28 days prior to interview was reported by 44% (95% CI 35%-54%), and sharing of any equipment including that used for drug preparation prior to injection was reported by 66% (95% CI 57%-76%). In North West Wales, syringe sharing is a common practice, and a high proportion of IDUs have been exposed to bloodborne viruses. Hepatitis B vaccination coverage within this population appears to be low and needs to be increased. Further efforts are needed to improve the availability of clean injecting equipment.

Adult↗
PubMed2003

Cranial cruciate ligament injury in the dog: pathophysiology, diagnosis and treatment.

Cranial cruciate ligament (CCL) disease in the dog is a multifactorial complex problem that requires a thorough understanding of the biomechanics of the stifle joint to be understood. Successful treatment of rupture of the CCL should be based on managing underlying anatomical and conformational abnormalities rather than attempting to eliminate the tibial cranial drawer sign. The cranial and caudal cruciate ligaments, the patella ligament and quadriceps mechanism, the medial and lateral collateral ligaments, the medial and lateral menisci and the joint capsule provide stability of the joint and load-sharing. The function of the stifle is also significantly influenced by the musculature of the pelvic limb. An active model of biomechanics of the stifle has been described that incorporates not only the ligamentous structures of the stifle but also the forces created by weight-bearing and the musculature of the pelvic limb. This model recognises a force called cranial tibial thrust, which occurs during weight-bearing, and causes compression of the femoral condyles against the tibial plateau. In middle-aged, large-breed dogs, forces acting on the CCL together with conformation-related mild hyperextension of the stifle and slightly increased tibial plateau slopes are suspected to cause progressive degeneration of the ligament. Palpation of craniolateral stifle laxity has become pathognomonic for CCL rupture; however, chronic periarticular fibrosis, a partial CCL rupture, and a tense patient, may make evaluation of instability of the stifle difficult. Surgical treatment is broadly separated into three groups: intracapsular, extracapsular, and tibial osteotomy techniques. Tibial osteotomy techniques do not serve to provide stability of the stifle but rather alter the geometry of the joint to eliminate cranial tibial thrust such that functional joint stability is achieved during weight-bearing. Visualisation of both menisci is a critical aspect of CCL surgery, irrespective of the technique being performed. Regardless of the surgical technique employed, approximately 85% of dogs show clinical improvement. However, many of these dogs will demonstrate intermittent pain or lameness. Post-operative management is an integral part of the treatment of CCL rupture, and significant benefits in limb function occur when formalised post-operative physiotherapy is performed.

Journal Article↗
PubMed2002

Statin use, hyperlipidaemia, and the risk of breast cancer.

Hydroxymethyl glutaryl coenzyme A inhibitors ("statins") are carcinogenic in rodents and an increased incidence of breast cancer was reported among pravastatin users in one randomised trial. We conducted a case-control study in the General Practice Research Database to evaluate the risk of breast cancer among 50- to 79-year old women treated with statins for hyperlipidaemia. Case and control women were matched by age, general practice, duration of prescription history in the General Practice Research Database, and index date. Adjusting for history of benign breast disease, body mass index, and use of hormone replacement therapy, women currently treated with statins had an estimated relative risk for breast cancer of 1.0 (95% confidence interval 0.6-1.6) compared to women without hyperlipidaemia. Untreated hyperlipidaemia was associated with an increased risk of breast cancer (estimated relative risk 1.6; 95% confidence interval 1.1-2.5). The estimated relative risk among women currently receiving only non-statin lipid-lowering drugs was similar to that of women with untreated hyperlipidaemia (1.8; 95% confidence interval 0.9-3.4). We found no evidence for an increasing trend in breast cancer risk with increasing duration of statin use (median duration 1.8 years, maximum 8.6 years).

Aged↗
PubMed2002

The effect of maternal prolactin infusion during pregnancy on fetal adipose tissue development.

The present study determines whether maternal administration of prolactin (PRL) to dams promotes the abundance of the brown adipose tissue-specific uncoupling protein-1 (UCP1) in fetal and neonatal rat pups. Recombinant PRL (24 micro g/kg per day), or an equivalent volume of saline, were infused into dams (n=19 per group) throughout pregnancy from 12 h after mating. Interscapular brown adipose tissue was sampled either from fetuses at 19.5 days of gestation (term=21.5 days) or from neonatal rat pups at approximately 18 h after birth. The abundance of UCP1 was determined by immunoblotting on adipose tissue samples from individual pups and pooled from groups of pups. This analysis was complemented by immunocytochemistry on representative adipose tissue samples. Maternal PRL infusion resulted in a greater abundance of UCP1 in fetal rats at 19.5 days of gestation (control: 97.2+/-8.4% reference; PRL: 525.6+/-74.4% reference; P<0.001) and in neonates 18 h after birth. In contrast, the abundance of the outer mitochondrial membrane protein voltage-dependent anion channel was unaffected by PRL. Neonatal adipose tissue sampled from pups born to PRL-infused dams possessed fewer lipid droplets, but more UCP1, as determined by immunocytochemistry. Fetal, but not maternal, plasma leptin concentrations were also increased by maternal PRL administration. In conclusion, as rats are altricial, and the potential thermogenic activity of brown adipose tissue develops over the first few days of postnatal life, these changes prior to, and at the time of, birth implicate PRL in fetal and neonatal adipose tissue maturation.

Adipose Tissue, Brown↗
PubMed2001

Impact of patient characteristics on the risk of influenza/ILI-related complications.

BACKGROUND: We sought to quantify the impact of patient characteristics on complications and health care costs associated with influenza and influenza-like illness (ILI) in a nonelderly population. METHODS: Patients with medical reimbursement claims for influenza in the 1996-1997 season were identified from the automated database of a large private New England Insurer (NEI). Influenza care during the 21- day follow-up period was characterized according to age, gender, vaccine status, co-morbidities, prior influenza/ILI episodes, treatments, and recent health care costs and related diagnoses. RESULTS: There were 6,241 patients. Approximately 20% had preexisting chronic lung disease. Overall, 23% had health care services for possible complications, among which respiratory diagnoses were the most common (13%). Two percent of the influenza/ILI episodes involved hospitalization, with a median stay of five days. Factors most strongly predictive of hospitalizations and complications were preexisting malignancy (hospitalizations OR = 3.7 and complications OR = 2.4), chronic heart disease (OR = 3.2 and OR = 1.8), diabetes (OR = 2.2 and OR = 1.7) and recent illnesses that would have counted as complications had they occurred during an influenza/ILI episode (hospitalizations OR = 3.2 and complications OR = 1.5). The same factors affected influenza-related costs and total costs of care as dramatically as they affected complication rates. CONCLUSIONS: Influenza/ILI-related costs are driven by the characteristics that predict complications of influenza. Patients with chronic illness and those with recent acute respiratory events are the most likely to experience complications and hospitalizations.

Adolescent↗
PubMed2001

Left ventricular stroke volume in the fetal sheep is limited by extracardiac constraint and arterial pressure.

1. Extracardiac constraint and sensitivity to arterial pressure may be critical factors that limit the functional reserves of the developing fetal heart in utero. We hypothesise that extracardiac constraint is the predominant factor that limits fetal stroke volume (SV). To test this hypothesis we studied six chronically instrumented fetal sheep to determine the relative roles that extracardiac constraint and arterial pressure play in determining left ventricular (LV) function. 2. Pregnant ewes (128-131 days gestation, term = 147 days) were anaesthetised (5 mg kg(-1) Propofol I.V., then 1.5 % halothane, 50 % O(2), balance N(2)O by inhalation) and instrumented using sterile surgical techniques to record LV end-diastolic pressure (P(lved)), aortic pressure (P(ao)), pericardial pressure (P(per)), and LV SV. 3. After a minimum of 72 h recovery, LV function was assessed by altering fetal blood volume to vary P(lved). Ventricular function curves were generated using two measures of ventricular function, SV and stroke work index (SWI = SV x P(ao)), and two measures of ventricular filling, P(lved) and LV end-diastolic transmural pressure (P(lved,tm) = P(lved) - P(per)). 4. Although decreasing P(lved) from the resting level decreased SV, increasing P(lved) from the resting level did not increase SV because the ventricular function curve plateaued. This plateau was not explained solely by an increase in aortic pressure, as the plateau remained present in the SWI versus P(lved) curve. When extracardiac constraint was accounted for (SV against P(lved,tm)), the plateau was largely eliminated (approximately 80 %). The remaining portion of the plateau (approximately 20 %) was eliminated when both extracardiac constraint and arterial pressure were accounted for (SWI versus P(lved,tm)). 5. Thus, the major limitation upon LV function in the near-term fetus results from extracardiac constraint limiting ventricular filling while, at the same time, a much smaller limitation arises from increasing arterial pressure.

Animals↗
PubMed2001

A molecular mimic of phosphorylated prolactin markedly reduced tumor incidence and size when DU145 human prostate cancer cells were grown in nude mice.

Others have demonstrated the presence of an autocrine prolactin (PRL) growth loop in the normal human prostate. In this study we have used three human prostate cancer cell lines but have focused on the androgen-independent human prostate cancer cell line, DU145, to ask: (a) whether this autocrine growth loop is maintained beyond the loss of androgen sensitivity in the progression of prostate cancer; and (b) whether interruption of this growth loop by a PRL receptor antagonist, an S179D mutant PRL, could inhibit the formation of DU145-derived tumors. The autocrine loop was examined in most detail in the DU145 cell line but was demonstrated to be functional in all three of the lines by the reversible inhibition of growth in vitro by the S179D PRL receptor antagonist. To investigate the effect of S179D PRL on the growth of DU145 tumors in nude mice two sets of experiments were performed. In the first set, Alzet minipumps containing no PRL, wild-type (WT) PRL, or the S179D PRL (the last two delivering 4.56 microg/24 h and 4.26 microg/24 h, respectively), were implanted s.c. on day 1. On day 4, 5 x 10(6) DU145 cells were injected s.c. in the hindquarter. On day 22, the animals were killed, tumors were removed, measured, and subsequently fixed and processed for histological confirmation of tumor formation. The incidence of tumors in the no-PRL control group was 9/11 animals (82%). In the animals treated with WT PRL, the incidence was 8/10 (80%), whereas in the animals treated with the S179D PRL, the incidence was markedly reduced to 3/11 (27%). Although WT PRL had no effect on the incidence of tumors, the average size of the tumors increased from 25.8 +/- 5.99 mm(3) in controls to 66.66 +/- 18.06 mm(3) in WT PRL-treated animals. In the second set of experiments, 5 x 10(6) DU145 cells were injected on day 1. On day 18, Alzet minipumps containing no PRL, WT PRL, or S179D PRL were implanted. On day 42, the animals were killed and the tumors processed as before. S179D PRL caused a reduction in tumor size from 1731 +/- 283 mm(3) in the no-PRL controls to 1031 +/- 295 mm(3), whereas WT PRL slightly increased the size to 2118 +/- 630 mm(3). We conclude that PRL is used as an autocrine growth factor by human prostate cancer cells both in vitro and in vivo and that interruption of this growth loop in vivo inhibits tumor initiation and the growth of well-established tumors.

Androgens↗
PubMed2001

Lower prolactin bioactivity in unmedicated schizophrenic patients.

In previous work, prolactin (PRL) abnormalities of a lower bioassay (BA) to radioimmunoassay (RIA) ratio were found in schizophrenic patients. This line of research was extended in seven male patients with schizophrenia who were neuroleptic-free; seven male control subjects were also studied. PRL values were assessed by RIA and Nb(2) BA techniques. The schizophrenic group had a significantly lower PRL BA as compared to normal controls and a lower PRL ratio of BA/RIA. The lower ratio is consistent with an earlier finding and suggests that schizophrenic patients have different molecular forms of PRL than control subjects. This difference could be due to a disordered tuberoinfundibular dopamine system or the long-term effects of neuroleptic medications.

Adult↗
PubMed2001

Neural tube defects in relation to use of folic acid antagonists during pregnancy.

Periconceptional folic acid supplementation reduces the risk of neural tube defects (NTDs). To determine whether periconceptional exposure to folic acid antagonists (FAAs) might therefore increase the risk of NTDs, the authors examined data from an ongoing case-control study of birth defects (1979-1998) in the United States and Canada. They compared data on 1,242 infants with NTDs (spina bifida, anencephaly, and encephalocele) with data from a control group of 6,660 infants with malformations not related to vitamin supplementation. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors and about medication use. The adjusted odds ratios of NTDs related to exposure to FAAs (including carbamazepine, phenobarbital, phenytoin, primidone, sulfasalazine, triamterene, and trimethoprim) during the first or second months after the last menstrual period, compared with no use in either month, were 2.8 (95% confidence interval: 1.7, 4.6) for FAAs as a group, 4.8 (95% confidence interval: 1.5, 16.1) for trimethoprim (based on five exposed cases), and 6.9 (95% confidence interval: 1.9, 25.7) for carbamazepine (six exposed cases). These results are adjusted for region, interview year, periconceptional folic acid supplementation, maternal age, weight, education, and infections early in pregnancy. These findings suggest that a number of FAAs may increase NTD risk, and they provide estimates of risk for selected drugs.

Adult↗